|Publication number||US5741881 A|
|Application number||US 08/755,190|
|Publication date||21 Apr 1998|
|Filing date||25 Nov 1996|
|Priority date||25 Nov 1996|
|Also published as||CA2272944A1, CA2272944C, DE69723724D1, DE69723724T2, EP0948370A1, EP0948370B1, WO1998023307A1|
|Publication number||08755190, 755190, US 5741881 A, US 5741881A, US-A-5741881, US5741881 A, US5741881A|
|Inventors||Birendra K. Patnaik|
|Original Assignee||Meadox Medicals, Inc.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (23), Non-Patent Citations (10), Referenced by (190), Classifications (35), Legal Events (7)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates generally to bio-active coating compositions. More particularly, the present invention relates to improved bio-active coatings with polymer backbones having α,β-unsaturated carbonyl functionality therewithin. Bio-active agents are attached to these backbones via spacer groups which bind to the β-carbon of the α,β-unsaturated-carbonyl-functionality-containing backbones.
It is well known to use bio-active materials to coat structures to be introduced into a living system. Over the last 30 years, research into this area has become increasingly important with the development of various bio-compatible substrates for use in contact with blood, such as, for example, vascular grafts, artificial organs, endoscopes, cannulas, and the like.
While various materials have been used to make such substrates, synthetic polymers have been increasingly popular as the preferred materials due to their anti-thrombogenic and good mechanical properties. For example, polyurethane is a useful and effective material with a variety of clinical applications. Although synthetic polymers, such as, PTFE and polyurethane, are less thrombogenic than earlier materials, thrombus formation is still a problem. A thrombus is the formation of a solid body composed of elements of the blood, e.g., platelets, fibrin, red blood cells, and leukocytes. Thrombus formation is caused by blood coagulation and platelet adhesion to, and platelet activation on, foreign substances. Thus, thrombus formation is a serious complication in surgery and clinical application of artificial organs.
Various anti-thrombogenic agents, such as, heparin, have been developed and incorporated-into bio-compatible substrates to combat thrombus formation. In a living system, heparin inhibits the conversion of a pro-enzyme (prothrombin) to its active form (thrombin). Thrombin catalyzes a complicated biochemical cascade which ultimately leads to the formation of a thrombus.
Infection is also a serious concern for substrates to be implanted into a host organism. Bacterial, viral and other forms of infection may lead to life-threatening complications when a substrate is implanted into a host organism. Thus, binding of an anti-infection agent to a surface of an implantable substrate can reduce the risk of infection when a substrate is introduced into a host organism.
The art is replete with various procedures for grafting bio-active molecules onto polymer surfaces to prevent thrombus formation and/or infection. For example, bio-compatible polymer surfaces have been described with various benefits including decreased thrombogenicity, increased abrasion-resistance and improved hydrophilic lubricious properties. Alternatively, preparing polymeric surfaces to receive bio-active agents by plasma treatment is also well known in the art.
Furthermore, polymer coatings are described that include either covalently or ionically binding bio-active agents to substrate surfaces. For example, as discussed hereinbelow, photochemical reactions are described which covalently bind bio-active agents to substrate surfaces. Also, quartenary ammonium reagents are described which ionically bind a bio-active agent to a substrate.
Alternatively, various substrate surfaces have previously been described that are suitable for introducing into a biological system without pretreatment of any bio-active agent. For example, Yoda et al. in U.S. Pat. No. 5,061,777 disclose that polyurethanes and polyurethaneureas containing both hydrophilic and hydrophobic polyether segments are more anti-thrombogenic than substrates produced from either a hydrophilic or a hydrophobic polyol exclusively. Similarly, Elton in U.S. Pat. No. 5,077,352 discloses a method of forming a mixture of an isocyanate, a polyol and a poly(ethylene oxide) in a carrier liquid. This mixture is then heated and cured to form a coating of a polyurethane complexed with a poly(ethylene oxide) having good adherence to a substrate and good anti-friction properties.
A significant limitation of these bio-compatible polymer surfaces, however, is that they are not completely bio-compatible. Thrombus formation and infection continue to pose problems when a substrate is implanted within a host using these bio-compatible polymer surfaces. Thus, various alternative methods have been described for preparing the surface of a substrate to be implanted in a host organism to accept bio-active agents. Plasma treatment of substrate surfaces is one such method.
For example, Hu et al. in U.S. Pat. No. 4,720,512 disclose a method for imparting improved anti-thrombogenic activity to a polymeric support structure by coating it with an amine-rich material, e.g., a polyurethaneurea, introducing hydrophobic groups into the amine-rich surface coating through plasma treatment with fluorine compounds, and covalently bonding an anti-thrombogenic agent to the hydrophobic amine-rich surface.
Such a method for plasma treating a substrate surface is limited in its scope because it only works with certain substrates. Thus, it does not provide a general purpose coating composition that can bind to a variety of substrate surfaces. In an alternate approach, however, various methods have been described for binding bio-active agents directly to substrate surfaces.
For example, Solomon et al. in U.S. Pat. No. 4,642,242 disclose a process for imparting anti-thrombogenic activity to a polyurethane polymer material by coating a support structure with a protonated amine-rich polyurethaneurea, activating the amine moiety with an alkaline buffer, and covalently linking an anti-thrombogenic agent, e.g., heparin, to the polyurethaneurea with a reducing agent.
Bio-active agents bound directly to polymer backbones suffer from several limitations. First, because these bio-active agents are directly linked to the polymer backbone, their in vivo mobility is decreased. Second, the process of linking the bio-active agent to the polymer backbone may diminish the number of functional binding sites on the bio-active agent. Third, the bio-active agent's close proximity to the polymer backbone limits its ability to interact with its physiological substrates. Thus, for all of these reasons, coatings containing bio-active molecules bound directly to the polymer backbone are limited by the bio-active agent's decreased activity.
Accordingly, alternative methods have been developed for binding bio-active molecules to substrate surfaces. In particular, methods for ionically binding bio-active agents to a substrate via a quaternary ammonium compound have been described. See for example, Mano in U.S. Pat. No. 4,229,838, Williams et al. in U.S. Pat. No. 4,613,517, McGary et al. in U.S. Pat. No. 4,678,660, Solomon et al. in U.S. Pat. No. 4,713,402, and Solomon et al. in U.S. Pat. No. 5,451,424.
These methods, however, are severely limited because the bio-active agent is leached over time from the surface of the substrate. Thus, the protection afforded by the ionically bound bio-active agent to the substrate surface is transient at best. Accordingly, more permanent methods for binding bio-active molecules to substrate surfaces have also been developed. These methods include covalently binding a bio-active molecule, either directly, or via a spacer molecule, to a substrate surface.
For example, photochemical reactions have been described for preparing substrate surfaces to receive anti-thrombogenic agents. Kudo et al. in U.S. Pat. No. 4,331,697 disclose a method for imparting anti-thrombogenic activity to a biomedical material by directly linking a heparin derivative to the surface of the material via actinic radiation. Similarly, Kudo et al. also disclose coating a surface of a biomedical material with a polymer having a carboxylic acid halide group and/or a carboxylic anhydride functional group as a side chain that can react with a heparin derivative.
Alternatively, Guire et al. in U.S. Pat. Nos. 4,973,493 and 4,979,959 disclose methods for binding bio-active molecules to substrates using a linking moiety with functionalized end groups that are preferably activated by different signals. The linking moiety can covalently bind a bio-active molecule upon introduction of a first activation signal which activates the first functionalized end group. The linking moiety is further capable of covalently binding to the substrate upon introduction of a second, different, signal (photochemical) which activates the second functionalized end group.
Bichon et al. in U.S. Pat. No. 4,987,181 disclose a substrate having an adhesive film with anti-thrombogenic properties on its surface. This adhesive film is an olefinic copolymer having side groups distributed randomly on the main chain, wherein these side groups are carboxylic groups and groups of the formula --CONH--(CH2)n --NH--CH2 --R, wherein R is a heparin molecule or a depolymerization fragment of a heparin molecule. The adhesive film is deposited onto the substrate via photo-initiated polymerization of a suitable monomer. Thus, heparin, or a fragment thereof, is covalently linked to the substrate via an amine spacer.
Thus, various spacer molecules that link bio-active agents to polymer substrates have been described by the above-referenced studies. These studies indicate that bio-active agents, such as, for example, heparin bound to polymer coatings, retain more of their activity if they are tethered away from the surface of a substrate by a spacer. Although spacer molecules provide a means for optimizing the bio-activity of bio-active molecules bound to substrate surfaces, several problems persist in the photochemical reactions used to bind these bio-active molecules via spacers to substrate surfaces. Included among these problems are the ability of the bio-active molecule to withstand the photochemical signal used to bind it to the substrate surface, as well as the ability of the substrate to withstand photoradiation. For example, inert polymeric substrates, e.g., polytetrafluoroethylene, degrade when exposed to photochemical reactions and cannot be used therewith. Thus, attempts have been made to use spacer molecules to bind bio-active agents to substrate surfaces without photochemical reactive groups.
For example, Park et al. developed a new soluble segmented polyetherurethaneurea-poly(ethylene oxide)-Heparin graft copolymer with improved blood compatibility.
In particular, the new soluble graft copolymer composition is derived from a four step process, wherein heparin is immobilized onto a commercial preparation of a segmented polyetherurethaneurea (PUU) using hydrophilic poly(ethylene oxide) (PEO) spacers of different molecular weights. This new method includes (1) coupling hexamethyldiisocyanate (HMDI) to a segmented polyetherurethaneurea backbone through an allophanate/biuret reaction between the urethane/urea-nitrogen proton and one of the isocyanate groups on the HMDI. Next, (2) the free isocyanate groups attached to the backbone are then coupled to a terminal hydroxyl group on a PEO to form a PUU-PEO product. Next (3) the free hydroxyl groups of the PUU-PEO product are treated with HMDI to introduce a terminal isocyanate group. Finally, (4) the NCO functionalized PUU-PEO is then covalently bonded to reactive functional groups on heparin (--OH and --NH2) producing a PUU-PEO-Hep product. K. D. Park and S. W. Kim, "PEO-Modified Surfaces-In Vitro, Ex Vivo and In Vivo Blood Compatibility", in Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications 283, 293-295 (J. Milton Harris ed. 1992). This method will be referred to hereinafter as the "Park Method."
The Park Method suffers from several draw backs. In particular, because of the number of reactions steps involved in the Park Method, the synthesis of the coating composition is slow, inefficient and prone to side reactions which contributes to a low yield and an increase in the amount of cross-linked polymer.
In general, all of these disclosures have addressed substrate surfaces and/or coatings therefor which can exist within biological systems and in particular, can increase the anti-thrombogenicity of the surface of, e.g., medical substrates. These reactions, however, are generally slow, multi-step syntheses, and are characterized by side reactions which lead to low yields and formation of cross-linked polymers. In addition, these reactions cannot be universally applied to substrate surfaces. Thus, in particular, there is a need for a bio-active coating and process that can be used with a broad spectrum of substrate surfaces. In addition, there is a need particularly for bio-active coating compositions that have α,β-unsaturated functionality as a platform for binding bio-active agents to polymer backbones. There is also a need for a simplified method of preparing such bio-active coatings that provides higher yields with negligible cross-linking, in a shorter period of time. The present invention is directed toward providing a solutions therefor.
The present invention relates to a bio-active coating composition that is the reaction product of two different reactions. The first reaction includes reacting a bio-compatible polymer backbone having α,β-unsaturated carbonyl functionality with a hydrophilic spacer having at least one reactive functional group at its first and second ends. In this reaction, one of the reactive functional groups of the spacer reacts with a β-carbon of the carbonyl functionality to bond the spacer to the polymer backbone. The second reaction includes reacting a bio-active agent with a remaining unreacted reactive functional group of the spacer to covalently bind the bio-active agent to the spacer.
In another embodiment of the present invention, a coating composition is provided which includes a polymeric structure defined by a bio-compatible polymeric backbone having a carbonyl functionality and at least one pendant moiety bonded to a β-carbon of the carbonyl functionality. The pendant moiety is selected from the group consisting of:
wherein R1 is a hydrophilic spacer group selected from the group consisting of aliphatic hydrocarbons, poly(oxy olefins) hydrophilic polyethers, hydrophilic polyethylenes, modified polyolefins, aliphatic polyesters, polyamines, polysiloxanes, polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, polyamino acids, and linear polysaccharides; and R2 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotics, antibacterial agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
In yet another embodiment of the present invention, there is provided a method for preparing a bio-active polymer coating having a bio-active group covalently bonded through a spacer group to a polymer backbone. This method includes providing a polymer backbone having α,β-unsaturated carbonyl functionality therewithin; reacting a β-carbon of the carbonyl functionality with a hydrophilic spacer having at least one reactive functional group at its first and second ends to attach the hydrophilic spacer as a pendant group off of the backbone; and further reacting the pendant group with a bio-active agent to covalently bond the bio-active agent to the pendant group.
In a further embodiment of the present invention, there is provided a polymer-bound bio-active composition represented by the structure: ##STR1## wherein P is a biocompatible polymer backbone having a β-carbon derived from an α,β unsaturated carbonyl functionality. R1 is a hydrophilic spacer group having at least one reactive functional group at its first and second ends and is further selected from the group consisting of aliphatic hydrocarbons, poly(oxy olefins) hydrophilic polyethers, hydropbilic polyethylenes, modified polyolefins, aliphatic polyesters, polyamines, polysiloxanes, polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, polyamino acids, and linear polysaccharides. R2 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotics, antibacterial agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
Still further, there is provided a bio-active coating composition which is formed from a polymer backbone with α,β-unsaturated carbonyl functionality. The polymer backbone is formed from four reactions. In the first reaction, a poly diol is reacted with a methylene diisocyanate to form a NCO-terminated prepolymer. In the second reaction, an α,β-unsaturated carbonyl functionality is reacted with the NCO terminated prepolymer to form the polymer backbone. In the third reaction, the polymer backbone is reacted with a hydrophilic spacer group having at least one reactive functionality at its first and second ends. In the fourth reaction, a bio-active agent is reacted with an unreacted end of the hydrophilic spacer in the presence of an optional catalyst to covalently bond the bio-active agent to the polymer backbone via the hydrophilic spacer.
While this invention is satisfied by embodiments in many different forms, there will be described herein in detail preferred embodiments of the invention, with the understanding that the present disclosure is to be considered as exemplary of the principles of the invention and is not intended to limit the invention to the embodiments illustrated and described. The scope of the invention will be measured by the appended claims and their equivalents.
In accordance with the present invention, novel bio-active coatings are provided. More particularly, novel compositions and methods are provided for the synthesis of heparinized polyarethanes.
The bio-active coatings and method described herein are particularly advantageous over previously disclosed polymer coatings, especially the Park Method described hereinabove because the α,β-unsaturated carbonyl functionality of the polymer backbones of the present coatings provide more controlled and reproducible bio-active coatings. In addition, the properties of the bio-active coatings of the present invention can be varied easily, e.g., biostability, hydrophilicity etc. Also, the use of α,β-unsaturated carbonyl functionality in the present bio-active coatings increases the reaction efficiencies and reduces the reaction times in comparison to previously disclosed methods. Furthermore, the use of α,β-unsaturated carbonyl functionality in the backbone of the present coatings allows these reactions to be carried out at lower temperatures. Importantly, the α,β-unsaturated carbonyl functionality in the present backbones reduces the number of cross-links formed and provides higher polymer yields than previously described methods. Moreover, these bio-compatible α,β-unsaturated carbonyl functionality-containing polyurethane backbones are not commercially available and are described for the first time herein in connection with the present coatings.
In one embodiment of the present invention, there is provided a bio-active coating composition having a polymer backbone with α,β-unsaturated carbonyl functionality. This coating composition includes four reactions. The first reaction includes reacting a poly diol, such as for example polycarbonate (PC) diol with a diisocyanate functionality (II). Although the preferred polycarbonate diol (I) is described, any poly(diol) may be used that is reactive with the diisocyanate functionality to form an NCO-terminated prepolymer. Other poly(diols) include, for example, polyether(diol) and polyester(diol). Thus, as indicated below RM #1 illustrates the synthesis of prepolymer (III) from a polycarbonate(diol) and a methylene diisocyanate.
Reaction Mechanism (RM) #1 ##STR2## wherein, φ is an aromatic compound having, for example, six carbon atoms. As described above, in RM #1, the diisocyanate functionality is methylene diisocyanate, however, any diisocyanate may be used which is reactive with poly(diol) (I) to form the prepolymer (III).
In RM #1, the resulting NCO-terminated prepolymer (III) is then reacted with an α,β-unsaturated carbonyl functionality, such as for example composition (IV) as described below in RM #2:
RM#2 ##STR3## Composition (IV) can be any, α,β-unsaturated carbonyl functionality that is reactive with the prepolymer (III) to form intermediate (V).
Intermediate V is then heated to a temperature sufficient to cause CO2 to be removed from the polymer backbone as indicated below in RM #3. This temperature is below about 100° C. and preferably about 60° C.
RM #3 ##STR4##
The bio-compatible polymer backbone (VI) of the present invention may be any polymer backbone capable of entering into the reactions described herein. Preferred polymer backbones are polyurethanes including for example, polycarbonateurethaneureas, polyetherurethaneureas, and polyesterurethaneureas. The type of backbone will of course vary according to use, desired properties of the end product, as well as, the starting materials used to synthesize the backbone.
Polymer backbone (VI) is then reacted with a hydrophilic spacer group R1, such as poly(ethylene)oxide (PEO) having at least one reactive functionality at its first. and second ends as indicated below in RM #4:
RM #4 ##STR5##
The α,β-unsaturated carbonyl functionality contained within the bio-compatible polymer backbone is selected to participate in Michael addition-type reactions for bonding the spacer to the bio-compatible backbones. Thus, the incorporated carbonyl functionalities of the present polymer backbones include such α,β-unsaturated carbonyl functionalities which are reactive with the spacer and can bond the spacer to the backbone via the β-carbon of the carbonyl functionality. An example of such a carbonyl functionality is HOOC--CH═CH--COOH.
The above indicated reaction, i.e., RM #4, may take place in the presence of a hydrogen donating compound. Preferably, this hydrogen donating compound is an acid. More particularly, this acid is, for example, methanol or dilute fumaric acid.
Although the preferred hydrophilic spacer group, i.e., an me-terminated polyethylene oxide (PEO) spacer, is described, any spacer may be used which is reactive with the β-carbon of the α,β-unsaturated carbonyl functionality in the polymer backbone, as well as, a bio-active agent as described below in RM #5:
RM #5 ##STR6## wherein R1 is a spacer group and R2 is a bio-active agent.
In RM #5 described above, a bio-active agent, such as for example heparin is covalently bound to the intermediate (VIII) in the presence of an optional catalyst/dehydrating agent, such as, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). In non-aqueous organic solvents, many carbodiimides can be used, Such as for example dicyclohexyl carbodiimide. Alternatively, the intermediate VIII can be reacted with an aldehyde terminated heparin, e.g., a nitrous acid degraded heparin molecule.
The product (IX) of RM #5 indicated above is characterized by the chemical linkage, i.e., --NH--, between the spacer and the bio-active molecule, e.g., heparin, as well as between the polymer backbone and the spacer. This composition and its method of synthesis will be referred to hereinafter as "Inventive Embodiment I."
Inventive Embodiment I significantly improves upon previously described bio-active coating compositions and methods of making same, such as the Park Method described hereinabove. In particular, the method of the present invention provides for approximately a 100% increase in polymer yield, while significantly decreasing the amount of polymer cross-linking, i.e. unwanted side-reactions and cross-reactions, and without sacrificing heparin bio-activity.
The bio-active agent of the present invention is bound to the polymer backbone via a spacer group. The spacer group may include poly(oxy olefins) (e.g., poly(ethylene oxide)), aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, and linear or lightly branched polysaccharides. The spacer group is intended to be hydrophilic in order to take advantage of the natural repulsive forces of the hydrophobic polymeric substrate. The spacer group should have reactive functional groups on each end that are capable of reacting with and binding to the bio-compatible polymer backbone and bio-active agent, respectively. Preferably, the reactive functional group on each end of the spacer is, for example, an amine group. As stated above, an amino end-blocked poly(ethylene oxide) is a preferred example.
Moreover, hydrophilic poly(ethylene oxide) spacers are preferred because they have low interfacial free energy, lack binding sites, and exhibit highly dynamic motion. These characteristics are important because they increase the activity of a PEO-linked bio-active agent, e.g., heparin. See, K. D. Park et al., supra.
As previously described, the length of the spacer group may be used to control the bio-active agent's activity. It is known in the art that the anti-thrombogenic activity of heparin is increased when it is positioned a certain distance from the substrate to which it is bound. For example, in a comparison of polymeric substrate-spacer-heparin coatings using a C6 alkyl spacer, PEO 200, PEO 1000 and PEO 4000, the polymer-PEO 4000-Heparin surface maintained the highest bio-activity. See, K. D. Park et al., supra. Thus, methods are available in the art for controlling the activity of a polymer-bound bio-active agent. By utilizing such methods, one may determine the optimal length of the spacer. Accordingly, as used herein, "effective distance" means the distance between the bound bio-active agent and the polymer backbone which corresponds to a desired level of activity in the bio-active agent.
Thus, in the present invention, control over the bio-active agent's activity is achieved by varying the length, i.e., molecular weight, of the spacer group in Inventive Embodiment I. The spacer group may have a molecular weight of about 100 to about 200,000 daltons. Preferably, the spacer group has a molecular weight of about 200 to about 50,000 daltons. More preferably, the spacer group has a molecular weight of about 1,000 to about 4,000 daltons. Furthermore, the amount of the bio-active agent incorporated can also be controlled by the amount of the α,β-unsaturated carbonyl groups incorporated in the backbone polymer.
In accordance with the present invention, a significant reduction of thrombus formation and/or infection associated with the use of bio-compatible polymer backbones is achieved by combining an anti-thrombogenic and/or anti-infective agent in a coating to be applied to a host-contacting surface(s) of, for example, a medical device. A variety of anti-infective agents as known in the art may be used, including, antibiotics, such as penicillin and antibacterial agents such as silver sulfadiazine. Similarly, a variety of anti-thrombogenic agents known in the art may be used, including, heparin, hirudin, prostaglandin, urokinase, streptokinase, sulfated polysaccharide, and albumin. In some cases it may be desirable to provide either dual anti-infective or anti-thrombogenic action with two or more agents. Additionally, it may be desirable to combine an anti-infective and an anti-thrombogenic action by combining two or more of these different agents. The invention will be described in terms of the preferred heparin, a known anti-thrombogenic agent of known safety and high anti-coagulation activity, with the understanding that the invention contemplates any anti-thrombogenic and/or anti-infective agent which may be grafted to the polymeric substrate by the method of the present invention.
As described hereinabove, the bio-active coatings of the present invention are designed to be applied to the surface of host-contacting substrates, such as for example, a medical device. A medical device of the present invention may be any polymeric substrate compatible with one of the present bio-active coatings which, absent the coating, may lead to thrombus formation and/or infection when in contact with a body tissue or fluid. The polymeric substrate is preferably made from hydrophobic, inert polymeric material including, for example, polytetrafluoroethylene (ePTFE) and polyethyleneterephthalate (PET). Exemplary of, but not limited to, such medical devices are vascular access (arterial and venous) catheters, introducers, vascular grafts, endoprostheses, stents, stent-graft combinations, urinary catheters and associated substrates, such as drainage bags and connectors, and all abdominal cavity drainage tubing, bags and connectors. Preferred medical devices are, for example, ePTFE vascular grafts. For purposes of this invention, "vascular grafts" is meant to include endoprostheses.
In another embodiment of the present invention, a bio-active coating was prepared in a two-step reaction which is substantially identical to reactions described in RM#4 and RM #5. The first reaction includes reacting a bio-compatible polymer backbone having α,β-unsaturated carbonyl functionality (VI) with a hydrophilic spacer having at least one reactive functional group at its first and second ends (VII) as shown in RM #4. In this reaction, one of the reactive functional groups of the spacer reacts with a β-carbon of the carbonyl functionality to bond the spacer to the polymer backbone.
The second reaction, as indicated in RM #5, includes reacting a bio-active agent as described previously with a remaining unreacted functional group of the spacer in the presence of an optional catalyst to covalently bind the bio-active agent to the spacer.
In another embodiment of the invention, a coating composition is provided which is defined by a bio-compatible polymeric backbone having a carbonyl functionality and at least one pendant moiety bonded to a β-carbon of the carbonyl functionality. This pendant moiety is selected from the group consisting of:
wherein R1 and R2 are a spacer and a bio-active agent, respectively as defined hereinabove.
In a further embodiment of the invention, a method for preparing a bio-active polymer coating is described in which a bio-active group is covalently bonded through a hydrophilic spacer group to a polymer backbone. In particular, this method includes providing a polymer backbone having α,β-unsaturated carbonyl functionality therewithin as described previously. This polymer backbone may be any backbone capable of participating in these reactions. Preferably, the backbone of the present invention is hydrophobic, which will generate a repulsive force against the hydrophilic spacer, which as stated previously, will aide in tethering the spacer away from the backbone to increase the availability of the bio-active agent. A β-carbon of the carbonyl functionality is then reacted with a hydrophilic spacer as described above wherein the spacer has at least one reactive functional group at its first and second ends. When finished, this reaction leaves the spacer attached as a pendant group off of the backbone. The pendant spacer group is then reacted with a bio-active agent as described above to covalently bond the bio-active agent to the pendant group.
In the present invention, a catalyst which can drive the above-described reaction may be optionally used. A preferred catalyst is 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, although others are contemplated.
In yet another embodiment of the present invention, there is provided a polymer-bound bio-active composition represented by the following structure: ##STR7## wherein P is a bio-compatible polymer backbone, R1 is a hydrophilic spacer and R2 is a bio-active agent, as described previously.
In a further embodiment of the present invention, a bio-active coating composition includes a polymer backbone having α,β-unsaturated carbonyl functionality reacted with a hydrophilic spacer having at least one reactive functional group at its first and second ends and a bio-active agent which is covalently reactive with one of the reactive functional groups on the spacer. As used herein, "covalently reactive with" means that the bio-active agent is capable of forming a covalent bond with an unreacted end of the spacer.
A 20% solution of polycarbonate diol (PC diol, molecular weight 890) was made by adding 17.8 gm of PC diol to N,N-dimethyl acetamide (DMAC). A 20% solution of methylene diisocyanate (MDI) was made by adding 7.50 gm MDI to DMAC. A solution of 5% fumaric acid (FA) was made by adding 1.16 gm. FA to DMAC. The MDI solution was taken in a reaction vessel and maintained at 60° C. The PC diol solution was fed into the vessel over 15 minutes and the reaction continued until the desired NCO level was attained (0.134 μm NCO/gm solution). At this time, the fumaric acid solution, containing 0.038 gm dibutyltindiluarate catalyst, was added to the vessel over 15 minutes. This reaction mixture was held at 60° C. for 1 hour. The temperature was then increased to 70° C. for 4 hours. If the reaction mixture becomes viscous, 166 gm of DMAC may be added. The reaction mixture was maintained at 70° C. for an additional 2 hours. The heat was mined off and the reaction mixture was stirred for approximately 14 hours at room temperature. The reaction was then terminated by adding a terminating agent, such as for example 5 mM dibutyl amine (DBA) (0.65 gm in 5.0 gm DMAC) with stirring for 1 hour. Other terminating agents, such as for example, alcohols may also be used.
The polymer composition (hereinafter Composition A) was precipitated out of solution by adding it dropwise into 2.5 L reverse osmosis (RO) water. The precipitate was stirred for three hours in 2.5 L of RO water. The RO water was decanted and the precipitated polymer composition was cut into small pieces and stirred for approximately 14 hours in 1.5 L of RO water. The RO water was decanted and 1.5 L of flesh RO water was added and stirred for approximately 14 hours. The RO water was decanted and 1.0 L of flesh RO water was added and stirred for 2 hours. This procedure was repeated three times total. The RO water was decanted a final time and Composition A was allowed to air dry for approximately 60 hours. Composition A was then dried under vacuum at about 35°-40° C. for approximately 7 hours. Approximately 19.5 gm (dry weight) of Composition A was obtained.
A 5% solution was made of Composition A of Example 1 by adding 3.75 gm of Composition A to 75.0 gm of DMAC. A solution of a previously prepared amine-terminated poly(ethylene)oxide (PEO) (Jeffamine ED2001, molecular weight=2,000) was prepared by adding 30 gm of amine-terminated PEO to 270 gm DMAC.
Composition A and me-terminated PEO was mixed in an Erleumeyer flask in an oil bath at approximately 65° C. with stirring. Twenty-five (25) ml of anhydrous methanol was slowly added to the mixture over the course of 3-4 minutes. The flask was stoppered, maintained under a nitrogen blanket and stirred at 65° C. for 42 hours.
The solution was roto-evaporated to 83 gm. The roto-evaporated solution was then added to ether which caused a brown colored material to precipitate out of the solution. The precipitate was then caused to go back into solution when RO water was added. This solution was placed in a 500 ml Erlenmeyer flask and evaporated to dryness.
250 ml of isopropyl alcohol (IPA) was added to the Erlenmeyer flask and stirred at room temperature for approximately 30 minutes. Thereafter, a gummy, rubbery polymer composition was observed sticking to the flask while the IPA layer remained clear. The IPA layer was decanted and 150 ml of fresh IPA was added to the polymer-containing flask which was then stirred for approximately 30 minutes. The IPA layer was decanted off and 100 ml of fresh IPA was added to the polymer-containing flask and stirred for approximately 30 minutes. The IPA layer was decanted off and replaced with 150 ml RO water. The polymer-containing flask was stirred for 1 hour at room temperature. The polymer was filtered, washed with an additional 100 ml RO water and dried in a vacuum oven at about 35°-40° C. Approximately 3.5 gm of a brown colored rubbery polymer was obtained (hereinafter Composition B).
Approximately 1.5 gm of Composition B, prepared as described in Example 2, was dissolved in 28.5 gm DMAC and 1.0 gm RO water. In addition, a heparin solution was made by dissolving 0.6 Na-heparin (Sigma) in 6.0 gm RO water and then adding 193.4 gm anhydrous DMAC. The solution which contained Composition B was combined with the heparin solution at pH 9.54. The pH of the mixture was adjusted to pH 4.7 by dropwise addition of 1N HCL. A 3% (wt) EDC solution containing 0.096 gm EDC, 3.0 gm DMAC and 0.1 gm RO water was added to the Composition B-heparin mixture in 6 installments approximately every 30 minutes over 2.5 hours. After the first half hour, the pH of the mixture was raised to 7.62 by dropwise addition of 1N NaOH. After the EDC solution was completely added to the Composition B-heparin mixture, it was stirred for approximately 14 hours at room temperature.
The mixture was then roto-evaporated to 48.0 gm and then precipitated in 500 ml ether. The ether was decanted and 500 ml of RO water was added. The polymer was filtered and the water layer was centrifuged. The polymer pellet was washed with water and then combined with the filtered polymer material. All of the polymer material was transferred to a Teflon dish and was dried under vacuum at about 35°-40° C. Approximately 1.17 gm of the heparin bound polymer was obtained (hereinafter Compound C).
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4229838 *||3 Jul 1978||28 Oct 1980||Sumitomo Electric Industries, Ltd.||Vascular prosthesis having a composite structure|
|US4331697 *||2 Sep 1980||25 May 1982||Teijin Limited||Novel heparin derivative, method for production thereof, and method for rendering biomedical materials antithrombotic by use of the novel heparin derivative|
|US4521564 *||10 Feb 1984||4 Jun 1985||Warner-Lambert Company||Covalent bonded antithrombogenic polyurethane material|
|US4600652 *||1 Apr 1985||15 Jul 1986||Warner-Lambert Company||Permanently bonded antithrombogenic polyurethane surface|
|US4613517 *||12 Aug 1985||23 Sep 1986||Becton, Dickinson And Company||Heparinization of plasma treated surfaces|
|US4642242 *||19 Mar 1986||10 Feb 1987||Becton, Dickinson And Company||Permanently bonded antithrombogenic polyurethane surface|
|US4678660 *||14 Aug 1985||7 Jul 1987||Deseret Medical, Inc.||Thermoplastic polyurethane anticoagulant alloy coating|
|US4713402 *||30 Aug 1985||15 Dec 1987||Becton, Dickinson And Company||Process for preparing antithrombogenic/antibiotic polymeric plastic materials|
|US4720512 *||24 Mar 1986||19 Jan 1988||Becton, Dickinson And Company||Polymeric articles having enhanced antithrombogenic activity|
|US4786556 *||24 Jul 1987||22 Nov 1988||Becton, Dickinson And Company||Polymeric articles having enhanced antithrombogenic activity|
|US4973493 *||15 Oct 1987||27 Nov 1990||Bio-Metric Systems, Inc.||Method of improving the biocompatibility of solid surfaces|
|US4979959 *||5 May 1989||25 Dec 1990||Bio-Metric Systems, Inc.||Biocompatible coating for solid surfaces|
|US5028597 *||13 Apr 1990||2 Jul 1991||Agency Of Industrial Science And Technology||Antithrombogenic materials|
|US5061777 *||19 Jul 1990||29 Oct 1991||Nippon Zeon Co., Ltd.||Thromboresistant polyetherurethane compounds and process for its production|
|US5077352 *||23 Apr 1990||31 Dec 1991||C. R. Bard, Inc.||Flexible lubricious organic coatings|
|US5077372 *||20 Mar 1991||31 Dec 1991||Becton, Dickinson And Company||Amine rich fluorinated polyurethaneureas and their use in a method to immobilize an antithrombogenic agent on a device surface|
|US5132108 *||8 Nov 1990||21 Jul 1992||Cordis Corporation||Radiofrequency plasma treated polymeric surfaces having immobilized anti-thrombogenic agents|
|US5134192 *||14 Feb 1991||28 Jul 1992||Cordis Corporation||Process for activating a polymer surface for covalent bonding for subsequent coating with heparin or the like|
|US5171264 *||28 Feb 1990||15 Dec 1992||Massachusetts Institute Of Technology||Immobilized polyethylene oxide star molecules for bioapplications|
|US5244564 *||21 Feb 1990||14 Sep 1993||Siemens Aktiengesellschaft||Apparatus for electrolytic surface coating of pourable material and method for operating the apparatus|
|US5258041 *||19 Mar 1991||2 Nov 1993||Bio-Metric Systems, Inc.||Method of biomolecule attachment to hydrophobic surfaces|
|US5409696 *||22 Nov 1993||25 Apr 1995||Cordis Corporation||Radiofrequency plasma treated polymeric surfaces having immobilized anti-thrombogenic agents|
|US5451424 *||24 Nov 1992||19 Sep 1995||Becton Dickinson And Company||Anti-infective and antithrombogenic medical articles and method for their preparation|
|1||*||Heparin Immobilization Onto Segmented Polyurethaneurea Surfaces Effect of Hydrophilic Spacers, by Ki Dong Park, Teruo Okano, Chisato Nojiri, and Sung Wan Kim, Journal of Biomedical Materials Research, vol. 22, 977 992 (1988).|
|2||Heparin Immobilization Onto Segmented Polyurethaneurea Surfaces-Effect of Hydrophilic Spacers, by Ki Dong Park, Teruo Okano, Chisato Nojiri, and Sung Wan Kim, Journal of Biomedical Materials Research, vol. 22, 977-992 (1988).|
|3||*||In Vivo Nonthrombogenicity of Heparin Immobilized Polymer Surfaces by Chisato Nojiri, Ki Dong Park, David W. Grainger, Harvey A. Jacobs, Teruo Okano, Hitoshi Koyanagi and Sung Wan Kim; ASAIO Trans 36: M168 M172 (1990).|
|4||In Vivo Nonthrombogenicity of Heparin Immobilized Polymer Surfaces by Chisato Nojiri, Ki Dong Park, David W. Grainger, Harvey A. Jacobs, Teruo Okano, Hitoshi Koyanagi and Sung Wan Kim; ASAIO Trans 36: M168-M172 (1990).|
|5||*||PEO Modified Surfaces In Vitro, Ex Vivo, and In Vivo Blood Compatibility by Ki Dong Park and Sung Wan Kim in Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, 283 301 (1992).|
|6||PEO-Modified Surfaces-In Vitro, Ex Vivo, and In Vivo Blood Compatibility by Ki Dong Park and Sung Wan Kim in Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, 283-301 (1992).|
|7||*||SPUU PEO Heparin Graft Copolymer Surfaces: Patentcy and Platelet Deposition in Canine Small Diameter Arterial Grafts by Won Gon Kim, Ki Dong Park, Syed F. Mohammad and Sung Wan Kim; ASAIO Trans 37: M148 M149 (1991).|
|8||SPUU-PEO-Heparin Graft Copolymer Surfaces: Patentcy and Platelet Deposition in Canine Small Diameter Arterial Grafts by Won Gon Kim, Ki Dong Park, Syed F. Mohammad and Sung Wan Kim; ASAIO Trans 37: M148-M149 (1991).|
|9||*||Synthesis and Characterization of SPUU PEO Heparin Graft Copolymers, by Ki Dong Park, Al Zhi Piao, Harvey Jacobs, Teruo Okano and Sung Wan Dim, Journal of Polymer Science: Part A: Polymer Chemistry; vol. 29, 1725 1737 (1991).|
|10||Synthesis and Characterization of SPUU-PEO-Heparin Graft Copolymers, by Ki Dong Park, Al Zhi Piao, Harvey Jacobs, Teruo Okano and Sung Wan Dim, Journal of Polymer Science: Part A: Polymer Chemistry; vol. 29, 1725-1737 (1991).|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US6096525 *||26 Nov 1997||1 Aug 2000||Meadox Medicals, Inc.||Bonding bio-active materials to expanded polytetrafluoroethylene or polyethylene terephthalate via an isocyanate-terminated spacer|
|US6107416 *||1 Feb 1999||22 Aug 2000||Scimed Life Systems, Inc.||Polymer coatings grafted with polyethylene oxide chains containing covalently bonded bio-active agents|
|US6197051||11 Feb 1999||6 Mar 2001||Boston Scientific Corporation||Polycarbonate-polyurethane dispersions for thromobo-resistant coatings|
|US6491965||17 Dec 1996||10 Dec 2002||Hamilton Civic Hospitals Research Development, Inc.||Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates|
|US6562781||30 Nov 1995||13 May 2003||Hamilton Civic Hospitals Research Development Inc.||Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates|
|US6723121||27 Sep 2000||20 Apr 2004||Scimed Life Systems, Inc.||Polycarbonate-polyurethane dispersions for thrombo-resistant coatings|
|US7045585||20 Mar 2002||16 May 2006||Hamilton Civic Hospital Research Development Inc.||Methods of coating a device using anti-thrombin heparin|
|US7186789||11 Jun 2003||6 Mar 2007||Advanced Cardiovascular Systems, Inc.||Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings|
|US7301001||20 Dec 2006||27 Nov 2007||Advanced Cardiovascular Systems, Inc.||Bioabsorbable, biobeneficial polyester polymers for stent coatings|
|US7312299||20 Dec 2006||25 Dec 2007||Advanced Cardiovascular Systems, Inc.||Bioabsorbabl, biobeneficial polyester polymers for stent coatings|
|US7390333||10 Jan 2003||24 Jun 2008||Advanced Cardiovascular Systems, Inc.||Biodegradable drug delivery material for stent|
|US7396541||15 Sep 2005||8 Jul 2008||Advanced Cardiovascular Systems, Inc.||Heparin prodrugs and drug delivery stents formed therefrom|
|US7470283||10 Jan 2003||30 Dec 2008||Advanced Cardiovascular Systems, Inc.||Biodegradable drug delivery material for stent|
|US7563780 *||18 Jun 2004||21 Jul 2009||Advanced Cardiovascular Systems, Inc.||Heparin prodrugs and drug delivery stents formed therefrom|
|US7658880||29 Jul 2005||9 Feb 2010||Advanced Cardiovascular Systems, Inc.||Polymeric stent polishing method and apparatus|
|US7662326||27 Apr 2007||16 Feb 2010||Advanced Cardiovascular Systems, Inc.||Compositions containing fast-leaching plasticizers for improved performance of medical devices|
|US7699890||28 Jan 2004||20 Apr 2010||Advanced Cardiovascular Systems, Inc.||Medicated porous metal prosthesis and a method of making the same|
|US7708548||10 Apr 2008||4 May 2010||Advanced Cardiovascular Systems, Inc.||Molds for fabricating stents with profiles for gripping a balloon catheter|
|US7731890||15 Jun 2006||8 Jun 2010||Advanced Cardiovascular Systems, Inc.||Methods of fabricating stents with enhanced fracture toughness|
|US7740791||30 Jun 2006||22 Jun 2010||Advanced Cardiovascular Systems, Inc.||Method of fabricating a stent with features by blow molding|
|US7757543||13 Jul 2006||20 Jul 2010||Advanced Cardiovascular Systems, Inc.||Radio frequency identification monitoring of stents|
|US7758881||24 Mar 2005||20 Jul 2010||Advanced Cardiovascular Systems, Inc.||Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device|
|US7761968||25 May 2006||27 Jul 2010||Advanced Cardiovascular Systems, Inc.||Method of crimping a polymeric stent|
|US7763271||10 Aug 2007||27 Jul 2010||Abbott Cardiovascular Systems Inc.||Polymeric micelle-based local delivery methods and devices|
|US7794495||17 Jul 2006||14 Sep 2010||Advanced Cardiovascular Systems, Inc.||Controlled degradation of stents|
|US7794776||29 Jun 2006||14 Sep 2010||Abbott Cardiovascular Systems Inc.||Modification of polymer stents with radiation|
|US7819914 *||16 Dec 2008||26 Oct 2010||Cordis Corporation||Adhesion promoting primer for coated surfaces|
|US7823263||9 Jul 2007||2 Nov 2010||Abbott Cardiovascular Systems Inc.||Method of removing stent islands from a stent|
|US7829008||30 May 2007||9 Nov 2010||Abbott Cardiovascular Systems Inc.||Fabricating a stent from a blow molded tube|
|US7842737||29 Sep 2006||30 Nov 2010||Abbott Cardiovascular Systems Inc.||Polymer blend-bioceramic composite implantable medical devices|
|US7867547||19 Dec 2005||11 Jan 2011||Advanced Cardiovascular Systems, Inc.||Selectively coating luminal surfaces of stents|
|US7875233||18 Jul 2005||25 Jan 2011||Advanced Cardiovascular Systems, Inc.||Method of fabricating a biaxially oriented implantable medical device|
|US7875283||16 Jun 2005||25 Jan 2011||Advanced Cardiovascular Systems, Inc.||Biodegradable polymers for use with implantable medical devices|
|US7886419||18 Jul 2006||15 Feb 2011||Advanced Cardiovascular Systems, Inc.||Stent crimping apparatus and method|
|US7901452||27 Jun 2007||8 Mar 2011||Abbott Cardiovascular Systems Inc.||Method to fabricate a stent having selected morphology to reduce restenosis|
|US7923022||13 Sep 2006||12 Apr 2011||Advanced Cardiovascular Systems, Inc.||Degradable polymeric implantable medical devices with continuous phase and discrete phase|
|US7951185||6 Jan 2006||31 May 2011||Advanced Cardiovascular Systems, Inc.||Delivery of a stent at an elevated temperature|
|US7951194||22 May 2007||31 May 2011||Abbott Cardiovascular Sysetms Inc.||Bioabsorbable stent with radiopaque coating|
|US7955381||29 Jun 2007||7 Jun 2011||Advanced Cardiovascular Systems, Inc.||Polymer-bioceramic composite implantable medical device with different types of bioceramic particles|
|US7959857||1 Jun 2007||14 Jun 2011||Abbott Cardiovascular Systems Inc.||Radiation sterilization of medical devices|
|US7959940||30 May 2006||14 Jun 2011||Advanced Cardiovascular Systems, Inc.||Polymer-bioceramic composite implantable medical devices|
|US7964210||31 Mar 2006||21 Jun 2011||Abbott Cardiovascular Systems Inc.||Degradable polymeric implantable medical devices with a continuous phase and discrete phase|
|US7967998||3 Jan 2008||28 Jun 2011||Advanced Cardiocasvular Systems, Inc.||Method of polishing implantable medical devices to lower thrombogenecity and increase mechanical stability|
|US7971333||30 May 2006||5 Jul 2011||Advanced Cardiovascular Systems, Inc.||Manufacturing process for polymetric stents|
|US7989018||31 Mar 2006||2 Aug 2011||Advanced Cardiovascular Systems, Inc.||Fluid treatment of a polymeric coating on an implantable medical device|
|US7998404||13 Jul 2006||16 Aug 2011||Advanced Cardiovascular Systems, Inc.||Reduced temperature sterilization of stents|
|US8003156||4 May 2006||23 Aug 2011||Advanced Cardiovascular Systems, Inc.||Rotatable support elements for stents|
|US8007529||1 Aug 2008||30 Aug 2011||Advanced Cardiovascular Systems, Inc.||Medicated porous metal prosthesis|
|US8016879||27 Jun 2007||13 Sep 2011||Abbott Cardiovascular Systems Inc.||Drug delivery after biodegradation of the stent scaffolding|
|US8017237||23 Jun 2006||13 Sep 2011||Abbott Cardiovascular Systems, Inc.||Nanoshells on polymers|
|US8034287||15 May 2007||11 Oct 2011||Abbott Cardiovascular Systems Inc.||Radiation sterilization of medical devices|
|US8043553||30 Sep 2004||25 Oct 2011||Advanced Cardiovascular Systems, Inc.||Controlled deformation of a polymer tube with a restraining surface in fabricating a medical article|
|US8048441||25 Jun 2007||1 Nov 2011||Abbott Cardiovascular Systems, Inc.||Nanobead releasing medical devices|
|US8048442||16 Sep 2008||1 Nov 2011||Abbott Cardiovascular Systems Inc.||Modified heparin-based coatings and related drug eluting stents|
|US8048448||15 Jun 2006||1 Nov 2011||Abbott Cardiovascular Systems Inc.||Nanoshells for drug delivery|
|US8099849||13 Dec 2006||24 Jan 2012||Abbott Cardiovascular Systems Inc.||Optimizing fracture toughness of polymeric stent|
|US8101196||25 Jun 2002||24 Jan 2012||Biointeractions, Ltd.||Polysaccharide biomaterials and methods of use thereof|
|US8109994||2 Jan 2008||7 Feb 2012||Abbott Cardiovascular Systems, Inc.||Biodegradable drug delivery material for stent|
|US8128688||19 Jun 2007||6 Mar 2012||Abbott Cardiovascular Systems Inc.||Carbon coating on an implantable device|
|US8172897||28 Jun 2004||8 May 2012||Advanced Cardiovascular Systems, Inc.||Polymer and metal composite implantable medical devices|
|US8173062||30 Sep 2004||8 May 2012||Advanced Cardiovascular Systems, Inc.||Controlled deformation of a polymer tube in fabricating a medical article|
|US8197879||16 Jan 2007||12 Jun 2012||Advanced Cardiovascular Systems, Inc.||Method for selectively coating surfaces of a stent|
|US8202528||5 Jun 2007||19 Jun 2012||Abbott Cardiovascular Systems Inc.||Implantable medical devices with elastomeric block copolymer coatings|
|US8241554||29 Jun 2004||14 Aug 2012||Advanced Cardiovascular Systems, Inc.||Method of forming a stent pattern on a tube|
|US8262723||9 Apr 2007||11 Sep 2012||Abbott Cardiovascular Systems Inc.||Implantable medical devices fabricated from polymer blends with star-block copolymers|
|US8293260||5 Jun 2007||23 Oct 2012||Abbott Cardiovascular Systems Inc.||Elastomeric copolymer coatings containing poly (tetramethyl carbonate) for implantable medical devices|
|US8293367||15 Jul 2011||23 Oct 2012||Advanced Cardiovascular Systems, Inc.||Nanoshells on polymers|
|US8333000||19 Jun 2006||18 Dec 2012||Advanced Cardiovascular Systems, Inc.||Methods for improving stent retention on a balloon catheter|
|US8343530||22 Dec 2006||1 Jan 2013||Abbott Cardiovascular Systems Inc.||Polymer-and polymer blend-bioceramic composite implantable medical devices|
|US8388679||8 Jun 2010||5 Mar 2013||Maquet Cardiovascular Llc||Single continuous piece prosthetic tubular aortic conduit and method for manufacturing the same|
|US8414642||1 Dec 2008||9 Apr 2013||Advanced Cardiovascular Systems, Inc.||Biodegradable stent of a polyorthoester polymer or a polyanhydride polymer|
|US8425591||11 Jun 2007||23 Apr 2013||Abbott Cardiovascular Systems Inc.||Methods of forming polymer-bioceramic composite medical devices with bioceramic particles|
|US8435550||13 Aug 2008||7 May 2013||Abbot Cardiovascular Systems Inc.||Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device|
|US8465789||18 Jul 2011||18 Jun 2013||Advanced Cardiovascular Systems, Inc.||Rotatable support elements for stents|
|US8470014||14 Aug 2007||25 Jun 2013||Advanced Cardiovascular Systems, Inc.||Stent-catheter assembly with a releasable connection for stent retention|
|US8486135||9 Apr 2007||16 Jul 2013||Abbott Cardiovascular Systems Inc.||Implantable medical devices fabricated from branched polymers|
|US8535372||18 Jun 2007||17 Sep 2013||Abbott Cardiovascular Systems Inc.||Bioabsorbable stent with prohealing layer|
|US8568469||28 Jun 2004||29 Oct 2013||Advanced Cardiovascular Systems, Inc.||Stent locking element and a method of securing a stent on a delivery system|
|US8585754||13 Jan 2012||19 Nov 2013||Abbott Cardiovascular Systems Inc.||Stent formed of a Biodegradable material|
|US8592036||20 Sep 2012||26 Nov 2013||Abbott Cardiovascular Systems Inc.||Nanoshells on polymers|
|US8596215||18 Jul 2011||3 Dec 2013||Advanced Cardiovascular Systems, Inc.||Rotatable support elements for stents|
|US8603530||14 Jun 2006||10 Dec 2013||Abbott Cardiovascular Systems Inc.||Nanoshell therapy|
|US8637110||18 Jul 2011||28 Jan 2014||Advanced Cardiovascular Systems, Inc.||Rotatable support elements for stents|
|US8696741||23 Dec 2010||15 Apr 2014||Maquet Cardiovascular Llc||Woven prosthesis and method for manufacturing the same|
|US8741379||18 Jul 2011||3 Jun 2014||Advanced Cardiovascular Systems, Inc.||Rotatable support elements for stents|
|US8747878||28 Apr 2006||10 Jun 2014||Advanced Cardiovascular Systems, Inc.||Method of fabricating an implantable medical device by controlling crystalline structure|
|US8747879||31 May 2006||10 Jun 2014||Advanced Cardiovascular Systems, Inc.||Method of fabricating an implantable medical device to reduce chance of late inflammatory response|
|US8752267||9 Aug 2013||17 Jun 2014||Abbott Cardiovascular Systems Inc.||Method of making stents with radiopaque markers|
|US8752268||9 Aug 2013||17 Jun 2014||Abbott Cardiovascular Systems Inc.||Method of making stents with radiopaque markers|
|US8778256||30 Sep 2004||15 Jul 2014||Advanced Cardiovascular Systems, Inc.||Deformation of a polymer tube in the fabrication of a medical article|
|US8808342||23 Apr 2013||19 Aug 2014||Abbott Cardiovascular Systems Inc.||Nanoshell therapy|
|US8846070||29 Jul 2008||30 Sep 2014||Advanced Cardiovascular Systems, Inc.||Biologically degradable compositions for medical applications|
|US8925177||17 Jul 2012||6 Jan 2015||Abbott Cardiovascular Systems Inc.||Methods for improving stent retention on a balloon catheter|
|US9038260||8 May 2014||26 May 2015||Abbott Cardiovascular Systems Inc.||Stent with radiopaque markers|
|US9072820||26 Jun 2006||7 Jul 2015||Advanced Cardiovascular Systems, Inc.||Polymer composite stent with polymer particles|
|US9127091||15 Jul 2011||8 Sep 2015||Biointeractions, Ltd.||Heparin coatings|
|US9173733||21 Aug 2006||3 Nov 2015||Abbott Cardiovascular Systems Inc.||Tracheobronchial implantable medical device and methods of use|
|US9180045 *||7 Apr 2011||10 Nov 2015||Mati Therapeutics Inc.||Treatment medium delivery device and methods for delivery of such treatment mediums to the eye using such a delivery device|
|US9198785||4 Dec 2013||1 Dec 2015||Abbott Cardiovascular Systems Inc.||Crush recoverable polymer scaffolds|
|US9248034||23 Aug 2005||2 Feb 2016||Advanced Cardiovascular Systems, Inc.||Controlled disintegrating implantable medical devices|
|US9259341||27 Feb 2013||16 Feb 2016||Abbott Cardiovascular Systems Inc.||Methods for improving stent retention on a balloon catheter|
|US9283099||25 Aug 2004||15 Mar 2016||Advanced Cardiovascular Systems, Inc.||Stent-catheter assembly with a releasable connection for stent retention|
|US9295570||23 Feb 2005||29 Mar 2016||Abbott Laboratories Vascular Enterprises Limited||Cold-molding process for loading a stent onto a stent delivery system|
|US9358325||22 Apr 2015||7 Jun 2016||Abbott Cardiovascular Systems Inc.||Stents with radiopaque markers|
|US9364498 *||22 Jun 2009||14 Jun 2016||Abbott Cardiovascular Systems Inc.||Heparin prodrugs and drug delivery stents formed therefrom|
|US9375445 *||22 Jun 2009||28 Jun 2016||Abbott Cardiovascular Systems Inc.||Heparin prodrugs and drug delivery stents formed therefrom|
|US9402753||22 Dec 2011||2 Aug 2016||Maquet Cardiovascular Llc||Woven prosthesis and method for manufacturing the same|
|US9468706 *||20 Mar 2015||18 Oct 2016||Abbott Cardiovascular Systems Inc.||Phosphoryl choline coating compositions|
|US9532888||31 Dec 2014||3 Jan 2017||Abbott Cardiovascular Systems Inc.||Stents with radiopaque markers|
|US20030021762 *||25 Jun 2002||30 Jan 2003||Luthra Ajay K.||Polysaccharide biomaterials and methods of use thereof|
|US20030097173 *||10 Jan 2003||22 May 2003||Debashis Dutta||Biodegradable drug delivery material for stent|
|US20030100487 *||11 Oct 2002||29 May 2003||Hamilton Civic Hospitals Res Dev., Inc.||Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates|
|US20030105518 *||10 Jan 2003||5 Jun 2003||Debashis Dutta||Biodegradable drug delivery material for stent|
|US20030113314 *||10 Oct 2002||19 Jun 2003||Hamilton Civic Hospitals Res Dev., Inc.||Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates|
|US20030124705 *||20 Mar 2002||3 Jul 2003||Berry Leslie Roy||Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates|
|US20040038932 *||7 Sep 2001||26 Feb 2004||Jack Hirsh||Antithrombotic compositions|
|US20040171747 *||4 Mar 2004||2 Sep 2004||Sheng-Ping Zhong||Polycarbonate-polyurethane dispersions for thrombo-resistant coatings|
|US20040253203 *||11 Jun 2003||16 Dec 2004||Hossainy Syed F.A.||Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings|
|US20050214339 *||29 Mar 2004||29 Sep 2005||Yiwen Tang||Biologically degradable compositions for medical applications|
|US20050232971 *||16 Jun 2005||20 Oct 2005||Hossainy Syed F||Biodegradable polymers for use with implantable medical devices|
|US20060014720 *||15 Sep 2005||19 Jan 2006||Advanced Cardiovascular Systems, Inc.||Heparin prodrugs and drug delivery stents formed therefrom|
|US20060041102 *||23 Aug 2004||23 Feb 2006||Advanced Cardiovascular Systems, Inc.||Implantable devices comprising biologically absorbable polymers having constant rate of degradation and methods for fabricating the same|
|US20060047336 *||25 Aug 2004||2 Mar 2006||Gale David C||Stent-catheter assembly with a releasable connection for stent retention|
|US20060058868 *||10 Sep 2004||16 Mar 2006||Gale David C||Compositions containing fast-leaching plasticizers for improved performance of medical devices|
|US20060224226 *||31 Mar 2005||5 Oct 2006||Bin Huang||In-vivo radial orientation of a polymeric implantable medical device|
|US20060229695 *||12 Apr 2005||12 Oct 2006||Brown Daniel G||Stents with profiles for gripping a balloon catheter and molds for fabricating stents|
|US20060265048 *||18 May 2005||23 Nov 2006||Advanced Cardiovascular Systems, Inc.||Polymeric stent patterns|
|US20060271168 *||22 May 2006||30 Nov 2006||Klaus Kleine||Degradable medical device|
|US20060292690 *||21 Jun 2006||28 Dec 2006||Cesco Bioengineering Co., Ltd.||Method of making cell growth surface|
|US20070032634 *||2 Aug 2005||8 Feb 2007||Gale David C||Method for extending shelf-life of constructs of semi-crystallizable polymers|
|US20070038290 *||15 Aug 2005||15 Feb 2007||Bin Huang||Fiber reinforced composite stents|
|US20070043426 *||16 Aug 2005||22 Feb 2007||Abbate Anthony J||Polymeric stent patterns|
|US20070045252 *||23 Aug 2005||1 Mar 2007||Klaus Kleine||Laser induced plasma machining with a process gas|
|US20070045255 *||23 Aug 2005||1 Mar 2007||Klaus Kleine||Laser induced plasma machining with an optimized process gas|
|US20070055364 *||23 Aug 2005||8 Mar 2007||Hossainy Syed F A||Controlled disintegrating implantable medical devices|
|US20070123689 *||20 Dec 2006||31 May 2007||Advanced Cardiovascular Systems, Inc.||Bioabsorbable, biobeneficial polyester polymers for stent coatings|
|US20070151961 *||3 Jan 2006||5 Jul 2007||Klaus Kleine||Fabrication of an implantable medical device with a modified laser beam|
|US20070156230 *||4 Jan 2006||5 Jul 2007||Dugan Stephen R||Stents with radiopaque markers|
|US20070179219 *||31 Jan 2006||2 Aug 2007||Bin Huang||Method of fabricating an implantable medical device using gel extrusion and charge induced orientation|
|US20070203568 *||27 Apr 2007||30 Aug 2007||Advanced Cardiovascular Systems, Inc.||Compositions containing fast-leaching plasticizers for improved performance of medical devices|
|US20070231365 *||31 Mar 2006||4 Oct 2007||Yunbing Wang||Degradable polymeric implantable medical devices with a continuous phase and discrete phase|
|US20070253999 *||31 May 2006||1 Nov 2007||Bin Huang||Method of fabricating an implantable medical device to reduce chance of late inflammatory response|
|US20070254012 *||28 Apr 2006||1 Nov 2007||Ludwig Florian N||Controlled degradation and drug release in stents|
|US20070271763 *||25 May 2006||29 Nov 2007||Bin Huang||Method of crimping a polymeric stent|
|US20070278720 *||19 Mar 2007||6 Dec 2007||Yunbing Wang||Implantable medical devices made from polymer-bioceramic composite|
|US20070280851 *||15 May 2007||6 Dec 2007||Abigail Freeman||Radiation sterilization of medical devices|
|US20070281073 *||1 Jun 2006||6 Dec 2007||Gale David C||Enhanced adhesion of drug delivery coatings on stents|
|US20070282426 *||22 Dec 2006||6 Dec 2007||Yunbing Wang||Polymer-and polymer blend-bioceramic composite implantable medical devices|
|US20070282431 *||30 May 2006||6 Dec 2007||Gale David C||Polymer-bioceramic composite implantable medical devices|
|US20070282433 *||1 Jun 2006||6 Dec 2007||Limon Timothy A||Stent with retention protrusions formed during crimping|
|US20070282434 *||19 Sep 2006||6 Dec 2007||Yunbing Wang||Copolymer-bioceramic composite implantable medical devices|
|US20070283552 *||30 May 2006||13 Dec 2007||Gale David C||Manufacturing process for polymeric stents|
|US20070286941 *||13 Jun 2006||13 Dec 2007||Bin Huang||Surface treatment of a polymeric stent|
|US20070299504 *||26 Jun 2006||27 Dec 2007||Gale David C||Polymer composite stent with polymer particles|
|US20070299511 *||27 Jun 2006||27 Dec 2007||Gale David C||Thin stent coating|
|US20080009938 *||7 Jul 2006||10 Jan 2008||Bin Huang||Stent with a radiopaque marker and method for making the same|
|US20080010947 *||13 Jul 2006||17 Jan 2008||Bin Huang||Reduced temperature sterilization of stents|
|US20080014244 *||13 Jul 2006||17 Jan 2008||Gale David C||Implantable medical devices and coatings therefor comprising physically crosslinked block copolymers|
|US20080021307 *||13 Jul 2006||24 Jan 2008||Abigail Freeman||Radio frequency identification monitoring of stents|
|US20080058916 *||31 May 2006||6 Mar 2008||Bin Huang||Method of fabricating polymeric self-expandable stent|
|US20080063685 *||13 Sep 2006||13 Mar 2008||Yunbing Wang||Degradable polymeric implantable medical devices with continuous phase and discrete phase|
|US20080091262 *||17 Oct 2006||17 Apr 2008||Gale David C||Drug delivery after biodegradation of the stent scaffolding|
|US20080103583 *||2 Jan 2008||1 May 2008||Debashis Dutta||Biodegradable drug delivery material for stent|
|US20080119438 *||25 Jul 2005||22 May 2008||Weitz Jeffrey I||Heparin compositions that inhibit clot associated coagulation factors|
|US20080243228 *||28 Mar 2007||2 Oct 2008||Yunbing Wang||Implantable medical devices fabricated from block copolymers|
|US20080254159 *||10 Apr 2008||16 Oct 2008||Daniel Gene Brown||Stents With Profiles For Gripping A Balloon Catheter And Molds For Fabricating Stents|
|US20080279898 *||29 Jul 2008||13 Nov 2008||Advanced Cardiovascular Systems Inc.||Biologically Degradable Compositions For Medical Applications|
|US20080299002 *||1 Jun 2007||4 Dec 2008||Abigail Freeman||Radiation sterilization of medical devices|
|US20080300670 *||30 May 2007||4 Dec 2008||Gueriguian Vincent J||Fabricating a stent from a blow molded tube|
|US20080306582 *||5 Jun 2007||11 Dec 2008||Yunbing Wang||Implantable medical devices with elastomeric copolymer coatings|
|US20080306591 *||5 Jun 2007||11 Dec 2008||Yunbing Wang||Implantable medical devices with elastomeric block copolymer coatings|
|US20080306592 *||5 Jun 2007||11 Dec 2008||Yunbing Wang||Elastomeric copolymer coatings for implantable medical devices|
|US20090082853 *||1 Dec 2008||26 Mar 2009||Advanced Cardiovascular Systems Inc.||Biodegradable drug delivery material for stent|
|US20090124984 *||23 Mar 2006||14 May 2009||Takao Hanawa||Medical Appliance and Process for Producing the Appliance|
|US20090258029 *||22 Jun 2009||15 Oct 2009||Abbott Cardiovascular Systems Inc.||Heparin Prodrugs and Drug Delivery Stents Formed Therefrom|
|US20090258047 *||22 Jun 2009||15 Oct 2009||Abbott Cardiovascular Systems Inc.||Heparin Prodrugs and Drug Delivery Stents Formed Therefrom|
|US20090258054 *||22 Jun 2009||15 Oct 2009||Abbotte Cardiovascular Systems Inc.||Heparin Prodrugs and Drug Delivery Stents Formed Therefrom|
|US20090258055 *||22 Jun 2009||15 Oct 2009||Abbotte Cardiovascular Systems Inc.||Heparin Prodrugs and Drug Delivery Stents Formed Therefrom|
|US20100152841 *||16 Dec 2008||17 Jun 2010||Vipul Dave||Adhesion promoting primer for coated surfaces|
|US20100179284 *||28 May 2008||15 Jul 2010||Dsm Ip Assets B.V.||Polymers with bio-functional self assembling monolayer endgroups for therapeutic applications and blood filtration|
|US20110202020 *||7 Apr 2011||18 Aug 2011||Qlt Inc.||Treatment medium delivery device and methods for delivery of such treatment mediums to the eye using such a delivery device|
|US20150328375 *||20 Mar 2015||19 Nov 2015||Abbott Cardiovascular Systems Inc.||Phosphoryl Choline Coating Compositions|
|EP2190441A1 *||28 May 2008||2 Jun 2010||DSM IP Assets B.V.||Polymers with bio-functional self assembling monolayer endgroups for therapeutic applications and blood filtration|
|EP2190441A4 *||28 May 2008||26 Mar 2014||Dsm Ip Assets Bv||Polymers with bio-functional self assembling monolayer endgroups for therapeutic applications and blood filtration|
|WO1998057671A2 *||17 Jun 1998||23 Dec 1998||Boston Scientific Corporation||Polycarbonate-polyurethane dispersions for thrombo-resistant coatings|
|WO1998057671A3 *||17 Jun 1998||15 Apr 1999||Boston Scient Corp||Polycarbonate-polyurethane dispersions for thrombo-resistant coatings|
|WO2003000305A2||26 Jun 2002||3 Jan 2003||Biointeractions Ltd||Polysaccharide biomaterials and methods of use thereof|
|WO2008150788A1 *||28 May 2008||11 Dec 2008||The Polymer Technology Group Incorporated|
|WO2012175923A1||22 Jun 2012||27 Dec 2012||Biointeractions Limited, University Of Reading||Biocompatible, biomimetic ampholyte materials|
|WO2014174237A1||28 Apr 2014||30 Oct 2014||Biointeractions Limited||Bioactive coatings|
|U.S. Classification||528/75, 536/21, 525/460, 525/453, 128/DIG.22, 514/56, 530/380|
|International Classification||C08G18/67, C08G18/83, A61L33/00, A61L29/08, A61L27/34|
|Cooperative Classification||C08G18/7671, Y10S128/22, C08G18/6755, C08G18/833, A61L29/085, A61L33/0029, C09D175/06, C09D5/1637, C08G81/00, C08G18/44, C08G18/10, A61L27/34|
|European Classification||A61L33/00H2F, A61L27/34, C08G18/67D2, C08G18/83C, A61L29/08B, C08G81/00, C08G18/76D2B, C08G18/10, C09D175/06, C08G18/44, C09D5/16C7|
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